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Endoglin As an Adhesion Molecule in Mature and Progenitor Endothelial Cells: a Function Beyond TGF-Β

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Endoglin As an Adhesion Molecule in Mature and Progenitor Endothelial Cells: a Function Beyond TGF-Β View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Digital.CSIC MINI REVIEW published: 30 January 2019 doi: 10.3389/fmed.2019.00010 Endoglin as an Adhesion Molecule in Mature and Progenitor Endothelial Cells: A Function Beyond TGF-β Elisa Rossi 1,2*, Carmelo Bernabeu 3 and David M. Smadja 1,2,4,5 1 Université Paris Descartes, Sorbonne Paris Cité, Paris, France, 2 Inserm UMR-S1140, Paris, France, 3 Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid, Spain, 4 Department of Hematology, AP-HP, Hôpital Européen Georges Pompidou, Paris, France, 5 Laboratory of Biosurgical Research, Carpentier Foundation, Hôpital Européen Georges Pompidou, Paris, France Endoglin (ENG) is a transmembrane glycoprotein expressed on endothelial cells that functions as a co-receptor for several ligands of the transforming growth factor beta (TGF-β) family. ENG is also a recognized marker of angiogenesis and mutations in the endoglin gene are responsible for Hereditary Hemorrhagic Telangiectasia (HHT) type 1, a vascular disease characterized by defective angiogenesis, arteriovenous malformations, Edited by: telangiectasia, and epistaxis. In addition to its involvement in the TGF-β family signaling Peter S. Steyger, pathways, several lines of evidence suggest that the extracellular domain of ENG has Oregon Health and Science University, a role in integrin-mediated cell adhesion via its RGD motif. Indeed, we have described United States a role for endothelial ENG in leukocyte trafficking and extravasation via its binding to Reviewed by: Eleni Papakonstantinou, leukocyte integrins. We have also found that ENG is involved in vasculogenic properties of Aristotle University of Thessaloniki, endothelial progenitor cells known as endothelial colony forming cells (ECFCs). Moreover, Greece Valerie Kouskoff, the binding of endothelial ENG to platelet integrins regulate the resistance to shear during University of Manchester, platelet-endothelium interactions under inflammatory conditions. Because of the need for United Kingdom more effective treatments in HHT and the involvement of ENG in angiogenesis, current Michelle Letarte, Hospital for Sick Children, Canada studies are aimed at identifying novel biological functions of ENG which could serve as *Correspondence: a therapeutic target. This review focuses on the interaction between ENG and integrins Elisa Rossi with the aim to better understand the role of this protein in blood vessel formation driven [email protected] by progenitor and mature endothelial cells. Specialty section: Keywords: endoglin, endothelial progenitors, EPC, ECFCs, HHT1, integrins, TGF-β This article was submitted to Translational Medicine, a section of the journal Frontiers in Medicine ENDOGLIN STRUCTURE AND FUNCTION Received: 27 June 2018 Endoglin (ENG; also known as CD105) is a type I transmembrane glycoprotein predominantly Accepted: 14 January 2019 expressed in endothelial cells (ECs) (1, 2) and endothelial colony-forming cells (ECFCs) Published: 30 January 2019 (3). It is known as an essential co-receptor for the transforming growth factor β (TGF- Citation: β) family, playing an important role in angiogenesis. At the cell surface, ENG associates Rossi E, Bernabeu C and Smadja DM with TGF-β type I receptors, including the ECs-specific ALK1 (activin receptor-like kinase (2019) Endoglin as an Adhesion β Molecule in Mature and Progenitor 1) and the ubiquitous ALK5, as well as to a TGF- type II receptor. In this receptor Endothelial Cells: A Function Beyond complex, ENG and ALK1 are able to bind to bone morphogenetic protein 9 (BMP9; TGF-β. Front. Med. 6:10. also known as growth differentiation factor 2 [GDF2]), a member of the TGF-β family, doi: 10.3389/fmed.2019.00010 with much higher affinity than to TGF-β1 and mediate its proliferation signal (4–7). Frontiers in Medicine | www.frontiersin.org 1 January 2019 | Volume 6 | Article 10 Rossi et al. Endoglin and Endothelial Progenitors Upon ligand binding, the TGF-β signaling receptor complex VASCULAR PATHOPHYSIOLOGY OF phosphorylates members of the Smad family of transcription ENDOGLIN IN HEREDITARY HEMORRAGIC factors which, in turn, undergo nuclear translocation to regulate TELANGECTASIA (HHT) gene expression (Figure 1A). In addition to the membrane bound form of endoglin, Hereditary Hemorrhagic Telangiectasia (HHT) is an a circulating form of the ENG ectodomain, was found to autosomal dominant disease with a prevalence of one case be released upon a C-terminal cleavage of ENG by matrix per 5,000–8,000 individuals (25, 26). HHT patients develop metalloproteinase 14 (MMP-14) (8, 9). Increased levels of muco-cutaneous lesions known as telangiectasia in the nose, circulating endoglin have been detected at early stages of mouth, and gastrointestinal tract, as well as larger AVMs preeclampsia (5, 10) in hypertensive or diabetic patients (11) in major organs such as the lung, liver, and brain (25). The and in certain cancer patients (12), suggesting its role as telangiectasia are comprised of fragile vessels that are susceptible a predictive biomarker in these pathologies. Interestingly, to rupture and hemorrhage, which means that HHT patients can a detailed characterization of plasma from women with suffer recurrent anemia following frequent and severe bleeding preeclampsia has revealed that circulating endoglin can be episodes. Mutations in the endoglin gene (ENG) are responsible complexed within exosomes, rather than as individual soluble for HHT type 1 (HHT1) (27), while mutations in activing endoglin (13). receptor-like kinase (ACVRL1 alias ALK1) are responsible for A pioneer article on human ENG described that this HHT2 (2, 27). Taken together, HHT1 and HHT2 account for glycoprotein is present on ECs as a dimer (two subunits more than 80% of all HHT cases, whereas a small number of of ∼90-kDa), each displaying the tripeptide arginine-glycine- patients show mutations in SMAD4 (MADH4) or in BMP9 aspartic acid (RGD) in the extracellular region of the protein gene (GDF2), which are responsible for less common HHT (1). The RGD motif and homologous sequences in mouse variants such as a combined syndrome with juvenile polyposis and pig are recognition motifs for cell surface integrins (JP-HHT) and HHT5, respectively (28, 29). Remarkably, all present in extracellular matrix proteins such as fibronectin, of these genes code for proteins involved in the TGF-β family tenascin, thrombospondin, vitronectin, von Willebrand factor signaling pathways (30). Nowadays, the most widely accepted as well as fibrinogen and prothrombin (14–16). Integrin- hypotheses for AVMs formation in HHT1 and HHT2 involves mediated adhesion is involved in hemostasis, thrombosis, and a “first hit” (gene haploinsufficiency) based on the loss of inflammation, processes in which the endothelium plays a one functional allele Eng+/− (HHT1) or ALK1+/− (HHT2), critical role. Therefore, the presence of the RGD motif within which causes a 50% reduction in protein expression, followed a hydrophilic environment (1) and its accessibility in the 3D by a “second hit” based on an angiogenic trigger such as structure of ENG (7), clearly suggest the involvement of ENG inflammation, hypoxia or vascular injury (31). Together, these in integrin binding, as postulated in early studies (17, 18). In events may induce a deficient endothelial function of ENG fact, endothelial endoglin binds to leukocyte integrins, allowing that could result in HHT vascular lesions. The relevant role leukocyte extravasation (19) suggesting a possible novel function of endoglin in the pathophysiology of the vascular system for ENG independent of TGF-β signaling (Figures 1B,C). Several is illustrated by the phenotype of different HHT1 animal lines of evidence support the role of ENG in leukocyte trafficking: models (32). While endoglin heterozygous mice are viable (i) ENG expression is markedly up regulated in endothelial cells and reproduce the vascular phenotype of HHT patients, total of inflamed tissues with an associated inflammatory cell infiltrate loss of ENG expression leads in mice to cardiovascular defects (19); (ii) ENG is up-regulated in the post-ischemic kidney and and embryonic death by mid-gestation (33–35). A conditional ENG-haploinsufficient mice are protected from renal ischemia- knock out mouse model for HHT1 has revealed that the reperfusion injury, due to a reduction of cellular inflammatory arteriovenous malformations (AVMs), induced upon ENG responses (20); (iii) Arterial, venous, and capillary endothelia in loss, appear to be the result of delayed vascular remodeling lymphoid organs are highly reactive with anti-ENG antibodies and inappropriate ECs proliferation responses (36). In ENG and a marked staining pattern is observed in high endothelial null mice, vasculogenesis does not seem affected, suggesting venules (21); and (iv) Although ENG is present throughout that ENG is not required for initial differentiation of ECs or the vascular endothelium, its expression, as compared to veins formation of a primitive vascular plexus. The yolk sac of Eng−/− or arteries, is stronger in capillaries, where most leukocyte embryos has enlarged fragile vessels, while the embryo proper infiltration to organs occurs. shows cardiac cushion defects and delayed maturation of major In addition to leukocytes, other cell types present in the vessels (34). The reason why the total loss of ENG expression circulatory system have also revealed
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